6HT0

Crystal structure of MLLT1 (ENL) YEATS domain in complexed with compound 94

Summary for 6HT0

• Entry DOI: 10.2210/pdb6ht0/pdb
• Related: 6HT1
• Descriptor: Protein ENL, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: transcription, yeats domain, enl, mllt1, chemical probe, inhibitor, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19319.19

Authors

Heidenreich, D.,Chaikuad, A.,Moustakim, M.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Fedorov, O.,Brennan, P.E.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-10-02, release date: 2018-10-17, Last modification date: 2024-01-24)

Primary citation

Moustakim, M.,Christott, T.,Monteiro, O.P.,Bennett, J.,Giroud, C.,Ward, J.,Rogers, C.M.,Smith, P.,Panagakou, I.,Diaz-Saez, L.,Felce, S.L.,Gamble, V.,Gileadi, C.,Halidi, N.,Heidenreich, D.,Chaikuad, A.,Knapp, S.,Huber, K.V.M.,Farnie, G.,Heer, J.,Manevski, N.,Poda, G.,Al-Awar, R.,Dixon, D.J.,Brennan, P.E.,Fedorov, O.
Discovery of an MLLT1/3 YEATS Domain Chemical Probe.
Angew. Chem. Int. Ed. Engl., 57:16302-16307, 2018

PubMed Abstract: YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.

PubMed: 30288907
DOI: 10.1002/anie.201810617

Experimental method

X-RAY DIFFRACTION (1.8 Å)